Pro-ferroptotic lipids as key control points for caveola formation and disassembly

Caveolae are specialized plasma membrane domains with a unique lipid composition. Lipid peroxidation has recently been implicated in triggering caveola disassembly, releasing cavin proteins to regulate oxidative-stress-associated cellular processes, particularly ferroptosis. Here, we investigated how specific lipids influence caveola formation and their response to oxidative stress. A targeted screening of pro-ferroptotic enzymes identified ACSL4, a key enzyme in synthesizing polyunsaturated fatty acid (PUFA)-linked phospholipids, and ether phospholipid biosynthesis enzymes as critical regulators of caveola formation. Membrane-incorporated omega-6 PUFAs promoted caveola formation, while their displacement by omega-3 PUFAs or monounsaturated fatty acids disrupted this process. Importantly, oxidation of omega-6 PUFA chains in phosphatidylethanolamine (PE) triggered caveola disassembly during lipid peroxidation, potentially by affecting cavin-membrane interactions. These findings unveil a new model for caveola formation and signaling, linking caveola dynamics to ferroptosis with pro-ferroptotic lipids as essential caveolar components and key control points for caveola disassembly under oxidative stress.